Much of the interest in bicontinuous cubic phase liquid crystals is a consequence of their unique structure. They are composed of mixtures of lipid and water arranged into bilayers. The bilayers, in turn, are twisted into a periodic, three-dimensional structure that minimizes the energy associated with bending the bilayers (i.e., minimize curvature energy). See Hyde, S., Andersson, S., Larrson, K., Blum, Z., Landh, T., Lidin, S., Ninham, B. W., The Language of Shape, Elsevier Press, New York, 1997. These structures are ‘honeycombed’ with bicontinuous domains of water and lipid reminiscent of an organic zeolite or highly structured micro emulsion. As such the structure can simultaneously accommodate water-soluble, lipid-soluble, and amphiphilic molecules, and provide pathways for diffusion of water-soluble, and lipid-soluble, materials. While there have been a number of proposed cubic phases, there are three common bicontinuous liquid crystals structures: Pn3m (D-surface), Ia3d (G-surface), and Im3m (P-surface). See Luzzati, V., Vargas, R., Mariani, P., Gulik, A., Delacroix, H., J. Mol. Biol., 1993, 229, 540-551. These structures can be difficult to express in rigorous mathematical terms. However, if expressed in terms of nodal surfaces, structure and shape can be approximated. See von Schnering, H. G., Nesper, R. Z., Phys. B-Condensed Matter, 1991, 83, 407-412. The phase behavior of a broad range of monoglycerides has been documented, particularly for monoolein. See Qiu, H., Caffrey, M., Biomaterials, 1999, 21(3), 223-234. Monoolein-based bicontinuous cubic liquid crystal phase have good temperature stability, high internal surface area, gel-like viscosity, relative insensitivity to salt and solvent compositions, and use low cost raw materials which make them practical for commercial applications. Monoolein naturally exhibits Pn3m and Ia3d structure, with Im3m structure present with the addition of proteins. See Rummel, G., Hardmeyer, A., Widmer, C., Chiu, M. L., Nollert, P., Locher, K. P., Pedruzzi, I., Landau, E. M., Rosenbusch, J. P., J. Structural Biology, 1998, 121, 82-91.
Cubic phase liquid crystals have been used in gel, dispersion and precursor form. ‘Gels’ are mixtures that contain a majority of the cubic phase liquid crystal. It is common for mixtures to exclusively contain cubic liquid crystal phase. Applications for these gels can range from drug delivery vehicles (See Shah, J. C., Sadhale, Y., Chilukuri, D. M., Adv. Drug Delivery Rev., 2001, 47(2-3), 229-250), to a matrix in which membrane proteins can be crystallized (See Landau, E., Rosenbusch, J., Proc. Natl. Acad. Sci. U.S.A., 1996, 93(25), 14532-14535), or in which mesoporous nanoparticles can be formed (See Cruise, N., Jansson, K., Holmberg, K., J. Colloid Interface Sci., 2001, 241(2), 527-529).
Nielsen, WO 98/47487, discloses compositions of bio-adhesive liquid crystal gels, including the cubic phase liquid crystals and precursors. Compositions include an active, a cubic phase forming lipid, and a structurant that is added without changing the structure of the liquid crystal. The structurant, as disclosed, imparts no properties to the composition other than a diluent. Further, no reference is made regarding the use of tethers as structurants.
Engstrom et al., U.S. Pat. No. 5,753,259, discloses a composition and method of use of liquid crystal gels, including cubic phase liquid crystals, for controlled release applications. The disclosed gels are fabricated from a mixture of lipid, solvent, and bioactive materials including nucleic acids. While the use of monoolein and phospholipid is disclosed, the express function is limited. For example, the disclosure does not disclose the ability to change compositional properties by the application of a stimulus, such as a change in pH.
‘Dispersions’ are particles of cubic liquid crystalline phase material that are often submicron in size. Particles are generally dispersed in a liquid medium and are often termed Cubosomes. High-pressure homogenization of a mixture of lipid and liquid generally makes colloidally unstable dispersions of cubic phase liquid crystals. This requires high pressures and numerous passes before homogeneous nanoparticle dispersions are produced (See Ljusberg-Wahren, H., Nyberg, L., Larsson, K., Chimica Oggi, 1996, 14, 40-43). Cubosomes have distinct practical advantages over vesicles and liposomes because cubosomes are an equilibrium phase (See Laughlin, R. G. Colloids and Surfaces A, 1997, 128, 27-38). Cubosomes also possess much greater internal surface area than vesicles or liposomes and are more resilient against degradation.
Anderson, WO 99/12640, and Landh et al., U.S. Pat. No. 5,531,925, disclose cubic phase compositions and preparations for delivery and uptake of active agents. The particles comprise a center containing liquid crystalline material. However, the particles disclosed in Anderson are coated with an exterior of solid particles. Further, the particles disclosed in Landh are coated with another liquid crystalline material.
‘Precursors’ are mixtures that are not cubic phase liquid crystals but form cubic phase liquid crystals as a consequence of a stimulus. Precursors can be used to dispense a mixture in a form that readily flows, but spontaneously converts to a more viscous liquid crystal gel or a more flowable dispersion with the stimulus at a target location. This is applicable to treatments for periodontal disease (See Norling, Tomas, Lading, Pia, Engstroem, Sven, Larsson, Kare, Krog, Niels, Nissen, Soeren Soe, J. Clin. Periodontol, 1992, 19(9, Pt. 2), 687-92.
Larsson et al., U.S. Pat. No. 5,196,201, discloses the preparation and composition of precursors used as implants to treat ailments such as the repair of bone tissue. These precursors are composed of a water-based liquid, lipid, and optionally a triglyceride mixed to form a more concentrated L2 or D phase, which flows more readily, and converts to cubic phase upon the addition of water. Leng et al., U.S. Pat. No. 5,593,663, discloses combinations and preparations of antiperspirant, which uptake sweat upon application to form a viscous liquid crystalline phase, including cubic phase. However, neither of these materials contains functionalization materials.
Cubic liquid crystalline phase materials are limited in use due to restriction of their natural, or unmodified, properties. For example, the natural properties of cubic phases limit the ability to solubilize active ingredients. In fact, broad classes of actives do not effectively load (or subsequently release) because the cubic phase lacks specific interaction with the loaded active. If the active is modified to effectively load in the cubic phase, it may lose its effectiveness. It has been suggested that the inclusion of zwitterionic phospholipids may cause increase in the absorption of active. Even if true, however, the results would be difficult to prove. (See Engstro, Sven, Norde, Tomas Petersson, Nyquist, Hakan, Eur. J. Pharm. Sci. 1999, 8(4), 243-254). It has also been suggested that the release of timolol maleate from a cubic phase liquid crystal could be affected by the inclusion of phospholipid in the cubic phase. However, the resulting concentrations of surfactant are insufficient to provide any practical value for many applications. (See Lindell, K., Engblom, J., Jonstromer, M., Carlsson, A., Engstrom, S., Progr. Colloid Polym. Sci, 1998, 108:111-118). Neither reference discloses the modification of cubic phase liquid crystal dispersions or precursors.
Further, there are no commercially convenient ways to provide specific targeting or enhanced deposition of actives from cubic phase. Finally, there are no cubic phases suitable for ‘on demand’ applications. “On demand’ refers to changes in the properties of cubic phase as a consequence of some stimulus, such as change in pH. As a result, a technique is needed to modify the cubic phase and significantly increase the utility of cubic phase.